Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A₁ and A₃receptors

Abstract

Renal ischemia and reperfusion during aortic and renal transplant surgery result in ischemic-reperfusion injury. Ischemic preconditioning and adenosine infusion before ischemia protect against ischemic-reperfusion injury in cardiac and skeletal muscle, but these protective phenomena have not been demonstrated in the kidney. Rats were randomized to sham operation, 45-min renal ischemia, ischemic preconditioning with four cycles of 8-min renal ischemia and 5-min reperfusion followed by 45-min renal ischemia, systemic adenosine pretreatment before 45-min renal ischemia, or pretreatments with selective adenosine receptor subtype agonists or antagonists before 45-min renal ischemia. Forty-five minutes of renal ischemia followed by 24 h of reperfusion resulted in marked rises in blood urea nitrogen and creatinine. Ischemic preconditioning and adenosine pretreatment protected renal function and improved renal morphology. A(1) adenosine receptor activation mimics and A(1) adenosine antagonism blocks adenosine-induced protection. In addition, A(3) adenosine receptor activation before renal ischemia worsens renal ischemic-reperfusion injury, and A(3) adenosine receptor antagonism protects renal function. We demonstrate for the first time that rat kidneys can be preconditioned to attenuate ischemic-reperfusion injury and adenosine infusion before ischemic insult protects renal function via A(1) adenosine receptor activation. Our data suggest that an A(1) adenosine agonist and A(3) adenosine antagonist may have clinically beneficial implications where renal ischemia is unavoidable.

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

“…Hence, dual acting agonists for A 1 and A 3 ARs might be useful for cardioprotection. In contrast to the effect of AR activation on the heart, pretreatment with an A 1 agonist or an A 3 antagonist protects the kidney from a subsequent prolonged ischemic insult [28]. The role of the A 3 AR in kidney function was further confirmed by the fact that A 3 AR knockout mice are protected against ischemia-and myoglobinuria-induced renal failure [29].…”

Bimodal Acute Effects of A1 Adenosine Receptor Activation on Na+/H+ Exchanger 3 in Opossum Kidney Cells

“…In kidneys subjected to ischemiareperfusion injury, preischemic administration of A 1 adenosine receptor agonists induced ischemic preconditioning, whereas postischemic A 2A adenosine receptor activation reduced tissue injury by attenuating the reperfusion phase of the injury process (6,9,10). Unlike A 1 or A 2 receptor agonists, A 3 adenosine receptor activation before renal ischemia worsened renal ischemia-reperfusion injury, whereas antagonism of A 3 adenosine receptors protected renal function (9).…”

Selective intrarenal human A1 adenosine receptor overexpression reduces acute liver and kidney injury after hepatic ischemia reperfusion in mice

“…Our laboratory previously showed that exogenous and endogenous A 1 adenosine receptor (A 1 AR) activation protected against renal IR injury in mice 8,9 as well as in rats 10,11 with reduced renal tubular necrosis, apoptosis, and inflammation. Moreover, endogenous A 1 ARs have an important role in protecting the liver against IR injury in mice.…”